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Climbing Fiber Synapses Rapidly Inhibit Neighboring Purkinje Cells Via Ephaptic Coupling

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Climbing Fiber Synapses Rapidly Inhibit Neighboring Purkinje Cells Via Ephaptic Coupling bioRxiv preprint doi: https://doi.org/10.1101/2019.12.17.879890; this version posted December 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Climbing fiber synapses rapidly inhibit neighboring Purkinje cells via ephaptic coupling Kyung-Seok Han*, Christopher H. Chen*, Mehak M. Khan, Chong Guo and Wade G. Regehr1 Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA *Co-first author 1Lead Contact Correspondence: [email protected] 1 bioRxiv preprint doi: https://doi.org/10.1101/2019.12.17.879890; this version posted December 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract Climbing fibers (CFs) from the inferior olive (IO) provide strong excitatory inputs onto the dendrites of cerebellar Purkinje cells (PC), and trigger distinctive responses known as complex spikes (CSs). We find that in awake, behaving mice, a CS in one PC suppresses conventional simple spikes (SSs) in neighboring PCs for several milliseconds. This involves a novel form of ephaptic coupling, in which an excitatory synapse nonsynaptically inhibits neighboring cells by generating large negative extracellular signals near their dendrites. The distance dependence of CS-SS ephaptic signaling, combined with the known divergence of CF synapses made by IO neurons, allows a single IO neuron to influence the output of the cerebellum by synchronously suppressing the firing of potentially over one hundred PCs. Optogenetic studies in vivo and dynamic clamp studies in slice indicate that such brief PC suppression can effectively promote firing in neurons in the deep cerebellar nuclei and motor thalamus. Introduction Climbing fiber (CF) synapses onto Purkinje cells (PCs) make essential contributions to cerebellar learning and cerebellar function. PCs are the sole outputs of the cerebellar cortex. Each PC receives a single powerful CF synapse from the inferior olive (Eccles et al., 1966; Szentágothai and Rajkovits, 1959). Activation of a CF onto a PC evokes a characteristic response known as a complex spike (CS) (Eccles et al., 1966; Fujita, 1968; Llinas and Sugimori, 1980) that arises from strong depolarization, dendritic calcium electrogenesis, and a sodium action potential followed by a series of spikelets (Davie et al., 2008; Eccles et al., 1966; Llinas and Nicholson, 1971; Llinas et al., 1968). CSs occur at 1-2 Hz and are readily distinguished from conventional sodium spikes known as simple spikes (SSs) (Eccles et al., 1966) that occur at frequencies of tens to over 100 Hz. Mossy fiber inputs to the cerebellar cortex activate granule cells (grCs), and tens of thousands of grCs form weak synapses onto each PC. It is thought that the cerebellum transforms mossy fiber inputs into PC outputs that serve as predictions of behavioral outcome (Medina, 2011). CFs provide instructive signals that regulate those grC to PC synapses that contribute to flawed predictions (Gilbert and Thach, 1977; Kitazawa et al., 1998; Lang et al., 2017). CSs are followed by a pause in SSs (Barmack and Yakhnitsa, 2003; Bell and Grimm, 1969; Granit and Phillips, 1956; Jin et al., 2017; Tang et al., 2017; Thach, 1967), allowing CFs to directly affect cerebellar output (Apps et al., 2018; Bengtsson et al., 2011; Blenkinsop and Lang, 2011; Eccles et al., 1966; Lang and Blenkinsop, 2011; Sudhakar et al., 2015; Tang et al., 2019; Tang et al., 2016; Yarden- Rabinowitz and Yarom, 2017). In addition, CF to PC synapses release so much glutamate that it slowly spills over to activate nearby molecular layer interneurons (MLIs) and Golgi cells (GCs) (Coddington et al., 2013; Eccles et al., 1966; Jorntell and Ekerot, 2003; Mathews et al., 2012; Nietz et al., 2017; Szapiro and Barbour, 2007). Thus, the CF plays a central role in cerebellar learning, regulates activity within the cerebellar cortex, and controls the output of the cerebellar cortex. 2 bioRxiv preprint doi: https://doi.org/10.1101/2019.12.17.879890; this version posted December 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Here we ask whether CF synapses can directly inhibit nearby PCs via ephaptic signaling. Ephaptic signaling occurs when extracellular potentials directly influence firing (Anastassiou et al., 2015; Anastassiou et al., 2011; Blot and Barbour, 2014; Furukawa and Furshpan, 1963; Han et al., 2018; Korn and Axelrad, 1980; Korn and Faber, 1975; Weiss and Faber, 2010). Most ephaptic signaling described previously involves changes in extracellular potential near the axon initial segment where action potential firing is initiated. For example, at synapses between cerebellar basket cells and PCs, current flow through potassium channels of a presynaptic specialization known as a pinceau produces depolarizing extracellular signals near the axon that transiently inhibit the target PC (Blot and Barbour, 2014; Korn and Axelrad, 1980). Ephaptic coupling also occurs between PCs to promote synchronous firing. During a SS, sodium channels in the initial segment generate a hyperpolarizing extracellular signal that can directly open sodium channels in the axons of neighboring PCs to promote spike initiation (Han et al., 2018). We hypothesized that CSs could also generate large extracellular signals that would influence the firing of nearby PCs via ephaptic signaling. We tested the hypothesis that CSs in one PC influence SS firing in neighboring PCs. Using in vivo multielectrode recordings, we found that CSs immediately suppress SSs in neighboring cells for about two milliseconds, after which SS firing in neighboring cells returns to baseline levels. We found that this suppression was a consequence of the complex spatiotemporal extracellular signals produced by CF activation. For CSs, the extracellular signals near the axons were not very effective at promoting SS firing in nearby PCs. Instead, the influence of the CF on nearby PCs was mediated by a novel form of ephaptic signaling whereby current flow through dendritic ionotropic glutamate receptors at a single CF synapse generates dendritically-localized extracellular hyperpolarization that reduces the firing of neighboring PCs. Based on the observed spread of ephaptic signaling (approximately 50 µm), the close spacing of PCs (Altman and Winfree, 1977), and the fact that IO neurons form CF synapses with multiple PCs (~7 PCs) (Sugihara et al., 2001), our findings suggest that a single IO cell can synchronously suppress PC firing in over 100 PCs. Dynamic clamp and optogenetic studies indicate that such brief inhibition of PC firing leads to transient disinhibition that can be highly effective at promoting firing in target cells in the deep cerebellar nuclei. Results In order to assess whether CSs in one cell influence SSs in neighboring cells, we recorded from pairs of Purkinje cells in awake, head-restrained animals on a cylindrical treadmill using a silicon probe with a linear array of electrodes (Figure 1A). Analysis was restricted to cases where the firing of individual PCs could be isolated on two or more electrodes. SSs occurred at much higher frequencies and had very different waveforms than CSs (Figure 1B). Following a CS there was a characteristic pause of SS firing in that same cell (Figure S2). To our surprise, CSs in one cell produced a short-latency transient decrease in SSs in a PC recorded on an adjacent site (Figures 1C-1G, S2B). CSs recorded on one electrode (Figure 1Ca) were used to align recordings from a second site (Figure 1Cb). It was immediately apparent from superimposed trials, (Figure 1Cb), a raster plot (Figure 1Cc), and a histogram (Figure 1Cd) that there were fewer spikes in PC2 3 bioRxiv preprint doi: https://doi.org/10.1101/2019.12.17.879890; this version posted December 18, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. immediately after the occurrence of the CS in PC1. This pause began at the onset of the CS in PC1, and persisted for approximately 2 ms (Figure 1Cd). Analysis of many pairs of PCs revealed that this decrease in firing was dependent on distance (Figure 1D). Suppression was largest for recordings from neighboring contacts (25 µm separation), was still apparent for cells separated by 50 µm, and absent for electrodes separated by 75 µm or more (Figure 1E). A CS in one cell suppressed SSs in neighboring cells with remarkable speed. A comparison of the CS waveform and SS histogram for a neighboring PC illustrates that SS suppression in neighboring cells begins at approximately the same time as the peak of the negative component of the CS, well before the positive component of the CS (Figure 1F). The average CS waveform and the average SS responses of neighboring cells showed similar timing (Figure 1G). This observation constrains the mechanism that allows CSs to influence the firing of neighboring PCs. The CS suppression of SSs in neighboring PCs raises two important questions. First, what is the mechanism? Second, what are the functional implications of this suppression? Based on the high packing density of PCs in the cerebellum (Altman and Winfree, 1977), and the fact that each IO neuron makes CF synapses with an average of 7 PCs, it is expected that a when a single IO neuron fires an action potential it could simultaneously suppress firing of up to 100 PCs. It is not known if transient PC suppression provides an effective means of activating targets in the deep cerebellar nuclei (DCN). We will begin by addressing the question of mechanism, and then return to the issue of functional significance. Mechanism of CS suppression of spiking in nearby PCs We considered a number of possible mechanisms that could allow CSs to suppress SSs in neighboring cells.
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